Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells

D. N. Carney, G. S. Ahluwalia, H. N. Jayaram, D. A. Cooney, D. G. Johns

Research output: Contribution to journalArticle

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Abstract

The antitumor activity of the antineoplastic agent, tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide), has previouly been shown to require intracellular anabolism of the drug to a nicotinamide adenine dinucleotide (NAD) analog (2-β-D-ribofuranosylthiazole-4-carboxamide adenine dinucleotide or 'tiazofurin adenine dinucleotide'), which then acts as a potent inhibitor of the target enzyme inosine monophosphate (IMP) dehydrogenase. Inhibition of the latter enzyme in turn brings about a profound depletion of intracellular guanosine nucleotides essential for tumor cell growth and replication. In the present study, the cytotoxicity and metabolism of tiazofurin have been examined in six human lung cancer cell lines. At the pharmacologically attainable drug concentration of 100 μM, colony survival was <1.5% in three cell lines ('sensitive'), while survival in the remaining three was > 50% ('resistant'). The metabolism of tritiated tiazofurin was examined at concentrations ranging from 0.5 to 100 μM following both brief (6 h) and protracted (14 d) exposures. The sensitive lines accumulated concentrations of tiazofurin adenine dinucleotide that were approximately 10 times those achieved by the resistant lines at both time points. We also observed tendencies for the sensitive cell lines to exhibit: (a) higher specific activities of NAD pyrophosphorylase, the enzyme required for the synthesis of tiazofurin adenine dinucleotide, (b) significantly lower levels of a phosphodiesterase which degrades the latter dinucleotide, (c) greater inhibition of the target enzyme IMP dehydrogenase, and (d) greater depressions of guanosine nucleotide pools after drug treatment. By contrast, the basal levels of IMP dehydrogenase and purine nucleotides in these six lines did not correlate in any obvious way with their responsiveness or resistance. The accumulation and monophosphorylation of parent drug were also not prognostic variables. These studies thus suggest that the extent of accumulation of tiazofurin adenine dinucleotide, as regulated by its synthetic and degradative enzyme activities, is the single most predictive determinant of the responsiveness of cultured human lung tumor cells to tiazofurin.

Original languageEnglish (US)
Pages (from-to)175-182
Number of pages8
JournalJournal of Clinical Investigation
Volume75
Issue number1
StatePublished - 1985
Externally publishedYes

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tiazofurin
Lung Neoplasms
Inosine Monophosphate
Oxidoreductases
Guanosine
Enzymes
Pharmaceutical Preparations
NAD
Nucleotides
Purine Nucleotides
Cell Line
Phosphoric Diester Hydrolases
Enzyme Inhibitors
Adenine
Antineoplastic Agents
Neoplasms
Lung

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Carney, D. N., Ahluwalia, G. S., Jayaram, H. N., Cooney, D. A., & Johns, D. G. (1985). Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. Journal of Clinical Investigation, 75(1), 175-182.

Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. / Carney, D. N.; Ahluwalia, G. S.; Jayaram, H. N.; Cooney, D. A.; Johns, D. G.

In: Journal of Clinical Investigation, Vol. 75, No. 1, 1985, p. 175-182.

Research output: Contribution to journalArticle

Carney, DN, Ahluwalia, GS, Jayaram, HN, Cooney, DA & Johns, DG 1985, 'Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells', Journal of Clinical Investigation, vol. 75, no. 1, pp. 175-182.
Carney, D. N. ; Ahluwalia, G. S. ; Jayaram, H. N. ; Cooney, D. A. ; Johns, D. G. / Relationships between the cytotoxicity of tiazofurin and its metabolism by cultured human lung cancer cells. In: Journal of Clinical Investigation. 1985 ; Vol. 75, No. 1. pp. 175-182.
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abstract = "The antitumor activity of the antineoplastic agent, tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide), has previouly been shown to require intracellular anabolism of the drug to a nicotinamide adenine dinucleotide (NAD) analog (2-β-D-ribofuranosylthiazole-4-carboxamide adenine dinucleotide or 'tiazofurin adenine dinucleotide'), which then acts as a potent inhibitor of the target enzyme inosine monophosphate (IMP) dehydrogenase. Inhibition of the latter enzyme in turn brings about a profound depletion of intracellular guanosine nucleotides essential for tumor cell growth and replication. In the present study, the cytotoxicity and metabolism of tiazofurin have been examined in six human lung cancer cell lines. At the pharmacologically attainable drug concentration of 100 μM, colony survival was <1.5{\%} in three cell lines ('sensitive'), while survival in the remaining three was > 50{\%} ('resistant'). The metabolism of tritiated tiazofurin was examined at concentrations ranging from 0.5 to 100 μM following both brief (6 h) and protracted (14 d) exposures. The sensitive lines accumulated concentrations of tiazofurin adenine dinucleotide that were approximately 10 times those achieved by the resistant lines at both time points. We also observed tendencies for the sensitive cell lines to exhibit: (a) higher specific activities of NAD pyrophosphorylase, the enzyme required for the synthesis of tiazofurin adenine dinucleotide, (b) significantly lower levels of a phosphodiesterase which degrades the latter dinucleotide, (c) greater inhibition of the target enzyme IMP dehydrogenase, and (d) greater depressions of guanosine nucleotide pools after drug treatment. By contrast, the basal levels of IMP dehydrogenase and purine nucleotides in these six lines did not correlate in any obvious way with their responsiveness or resistance. The accumulation and monophosphorylation of parent drug were also not prognostic variables. These studies thus suggest that the extent of accumulation of tiazofurin adenine dinucleotide, as regulated by its synthetic and degradative enzyme activities, is the single most predictive determinant of the responsiveness of cultured human lung tumor cells to tiazofurin.",
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